One idea of personalized cancer therapy is to identify specific subgroup of cancer patients that will benefit from specific therapeutic strategy. Recently the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research identified as the NCI's Provocative Questions. This research proposal addresses one such question How does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In addition, can the pathways that direct life span be used to identify potential molecular biomarkers and targets that can subsequently be used to identify specific groups of malignancies that will respond to targeted anticancer agents? This proposal clearly addresses this question in that we have previously shown that mice lacking mitochondrial Sirt3 gene develop estrogen receptor (ER) positive mammary tumors, a subtype of breast cancer predominantly observed in older women. Clinical data also suggest that there is a subgroup of ER positive luminal B human breast cancers that exhibit partial or complete loss of SIRT3 expression. In the last year the laboratory has made significant progress in delineating the underlying mechanistic relationship between reactive oxygen species (ROS) levels, HIF-1a signaling, and an in vivo phenotype permissive for breast carcinogenesis. Thus, it is proposed that there may be a specific subgroup of breast malignancies where loss of Sirt3 results in increased ROS and HIF1a that are early events in carcinogenesis and as such, agents that scavenge ROS molecules and/or inhibit HIF1a may prove to enhance cancer prevention or treatment. In this grant application we propose that mice lacking Sirt3 are a novel in vivo model in which to investigate the well established connection between decreased SIRT3 levels and ROS, HIF-1a, the Warburg effect, and breast malignancies. We hypothesize that agents thought to scavenge or decrease cellular ROS (O2-.) and/or inhibit HIF-1 activity will prevent tumors in Sirt3 knockout mice.